Dr Hendler held a longstanding position as professor at the University of Maryland where he was the Director of the Joint Institute for Knowledge Discovery and held joint appointments in the Department of Computer Science, the Institute for Advanced Computer Studies and the Institute for Systems Research. Hendler was the Director for Semantic Web and Agent Technology at the Maryland Information and Network Dynamics Laboratory, and a Fellow of the American Association for Artificial Intelligence and the British Computer Society.

In June 14, 2006, James A. Hendler was appointed senior constellation professor of the Tetherless World Research Constellation at Rensselaer Polytechnic Institute, and he became a professor at that institute starting on January 1, 2007. Hendler has appointments in Computer and Cognitive Sciences, and is also the Assistant Dean for Information Technology and Web Science.

Hendler helps lead the Tetherless World Constellation on increasing access to information at any time and place without the need for a “tether” to a specific computer or device. Researchers envision an increasingly web-accessible world in which personal digital assistants (PDAs), cameras, music-listening devices, cell phones, laptops, and other technologies converge to offer the user interactive information and communication. Hendler is also one of the directors of the Web Science Trust and a visiting professor for the Institute of Creative Technology at DeMontfort University.

He is also the Editor in Chief Emeritus of IEEE Intelligent Systems and is the first computer scientist to serve on the Board of Reviewing Editors for Science.

In October, 2010 Playboy magazine named Hendler to the "Honor Roll," their list of twenty of the most innovative US professors "Reinventing the Classroom."

He is a former member of the US Air Force Science Advisory Board and a former Chief Scientist of the Information Systems Office at the US Defense Advanced Research Projects Agency (DARPA). During his tenure there, he was responsible for projects such as CoABS - Control of Agent Based System, which led to the creation of other Agent-based projects: Taskable Agent Software Kit (TASK) and DARPA's Agent Markup Language (DAML) - the latter of which was involved in funding the emerging Semantic Web area.

Hendler was co-author, with Tim Berners-Lee and Ora Lassila, of the article "The Semantic Web" which appeared in Scientific American in 2001.